Inflammation is a phenomenon encountered in a variety of situations, including infections, transplantations, auto-immune disorders and following injury. There exists an immense range of distinct inflammatory reactions, each of which utilizes various immune mechanisms, such as memory T-cell and B-cells; cytokines and interleukins; preformed and synthesized chemical mediators, such as histamine, prostaglandins and leukotrienes; antibodies of different classes, as well as a whole host of disparate effector cells (e.g., killer cells, macrophages, neutrophils, basophils, eosinophils and the like).
Inflammatory diseases are among the most common maladies today. For example, asthma, a chronic inflammatory disorder of the airways, affects approximately 6–7% of the population of the U.S. (an estimated 17 million, according to a 1998 CDC forecast) and similar figures have been reported in other countries.
Asthma is a lung disease with the following characteristics: (1) airway obstruction that is reversible (but not completely so in some patients) either spontaneously or with treatment; (2) airway inflammation and (3) increased responsiveness to a variety of stimuli.
Airway inflammation contributes to the airway hyperresponsiveness, airflow limitation, respiratory symptoms and disease chronicity, which are characteristic of asthma (see Guidelines For The Diagnosis And Management of Asthma, Expert Panel Report 2, April 1997, NHLBI, NIH, Publication No. 97-4051, p.1). Asthma results from complex multi-cellular interactions among inflammatory cells, mediators, and other cells and tissues resident in the airway. Chronic inflammation of the airways is also a major cause of bronchial constriction, bronchial epithelial edema and mucus secretory abnormalities. Persistent airway inflammation is thought to lead to sub-basement membrane fibrosis which may cause permanent airway remodeling and chronic irreversible airway obstruction.
For these reasons, recent recommendations for asthma therapy have centered on the use of anti-inflammatory therapy. Anti-inflammatory therapy is designed to reduce the number of activated inflammatory cells, such as neutrophils, eosinophils, mast cells and lymphocytes and mediators such as cytokines and chemokines in airway tissues or secretions. Therapeutics that have been used in the treatment of airway inflammation include: glucocorticosteroids, cromones, theophylline and leukotriene modifiers (Inflammation in asthma: the cornerstone of the disease and target of therapy, W. W. Busse, 1998, J. Allergy Clin. Immunol. 102, S17–S22.).
Human glucocorticoid hormones of the adrenal cortex and their synthetic analogues have been the most widely adopted class of therapeutic agents used to treat a wide range of inflammatory conditions such as rheumatoid arthritis, lupus, inflammatory bowel disease, and asthma. These agents act via specific glucocorticoid membrane receptors found on a wide variety of cells, including those mediating inflammation. Once bound to the cell, their effects are mediated by a well-defined sequences of steps (see Glucocorticosteroids, RP Schleimer, p. 638–660 in Allergy, Principles and Practice ed. E. Middleton, Mosby, St. Louis, 1998) which culminates in the association of the glucocorticoid-receptor complex with cellular nuclear chromatin with the subsequent suppression of inflammatory genes as well as other effects. These actions are manifest on both developing and mature cells. This allows the use of glucocorticoid agents in both systemic and topical forms, including oral, intravenous, depot intramuscular, ophthalmic drops, cutaneous ointment and cream, suppository, retention enema, nasal spray, and by inhalation.
Despite their short-term effectiveness, however, glucocorticoids have significant long-term shortcomings. Glucocorticoids do not appear to alter the underlying pathologic processes, and discontinuance is generally followed by increasing symptoms and evidence for renewed airway inflammation (Juniper 1991, J. Allerg. Clin. Immunol., 87:483; Waalkens Am. Rev. Reso. Dis. 1993, 148:1252–57). Moreover, oral systemic corticosteroid treatment is complicated by multiple severe toxicities, including adrenal suppression, osteoporosis, cataract formation, glucose intolerance, obesity and hypertension.
Use of topical or organ-system directed delivery glucocorticosteroid hormones reduces but does not completely avoid all toxicity. For instance, even with inhaled glucocorticosteroids, there is a documented increased rate of cataract formation and growth retardation in children which is dose dependent. Furthermore, in many patients with more severe asthma, inhaled glucocorticosteroids appear to have efficacy only at elevated doses where significant systemic levels may appear via pulmonary absorption.
As a consequence of these shortcomings of glucocorticosteroids, a wide range of anti-inflammatory pharmaceuticals agents has been developed and proven effective for the treatment of a wide range of inflammatory diseases. These include anti-proliferative agents such as methotrexate which is used for treating rheumatoid arthritis and systemic lupus erythematosus and 6-mercapto purine analogues used for treating inflammatory bowel disease; alkylating agents such as cyclophosphamide used for treating systemic vasculitis; long-acting immunosuppressive or immunomodulating agents such as cyclosporine which is used for treating transplant rejection and sarcoidosis; gold salts used for treating rheumatoid arthritis, dapsone used for treating urticaria and cutaneous vasculitis; colchicine used for treating vasculitis and gout; and hydroxychloroquine (HCQ) used as a systemic anti-malarial agent for treating rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome. (Bell 1983, Am. J. Medicine, 75:46–51; Rothfield 1984, Am. J. Med., 85:53–56; Fox 1984, Am. J. Med., 85:62–67).
According to conventional usage, each and every one of these agents except HCQ has been administered systemically via oral or parenteral dosing only. HCQ has only been administered heretofore by oral dosing. Conversely, none has been dosed via a local, targeted administration, such as inhalational delivery, for several reasons. First, a large majority of these agents exert their effects on developing cells found in the marrow and spleen. Local, targeted administration cannot reach nor affect such cells; only with systemic administration can tissue levels sufficient to affect these cellular reservoirs be achieved. Second, unlike glucocorticosteroid hormones, a majority of these agents have little effect on mature inflammatory cells. Thus, local, targeted administration is-not viewed as conveying, any significant advantage in terms of therapeutic effect. Lastly, end-organ toxicity resulting from exposure to these agents may be appreciable and even life-threatening. Inasmuch as some of this toxicity is expressed by mucosal or serosal epithelial surfaces (e.g., stomatitis due to methotrexate and gold salts; gastrointestinal toxicity due to colchicine; bladder carcinoma due to cyclophosphamide), local, targeted administration of such agents has been viewed as unjustified in terms of presumed increased risk and the lack of a known advantage associated with direct application.
As a consequence, trials using gold salts, dapsone, methotrexate, cyclosporine and hydroxychloroquine (HCQ) as well as other anti-inflammatory treatments of asthma have uniformly relied on oral dosing (see Bernstein, J. Allerg. Clin., 1996, 98:317–24; Berlow, J. Allerg. Clin. Immunol. 1991, 87:710–15; Mullarkey NEJM 988, 38 (10):603–607; Alexander, Lancet, 1992, 339:324–328; Charous, 1990, Ann. Allergy, 68:80). Even newer pharmaceutical agents such as leukotriene receptor antagonists (zafirlukast and montelukast) and monoclonal anti-IgE antibodies are systemically administered due to lack of efficacy of local, targeted administration.
Only the anti-inflammatory pharmaceuticals nedocromil and cromolyn sodium are administered as local, targeted agents (via inhalation) due to the fact that these agents are only poorly absorbed by the gastrointestinal tract after oral dosing. These agents are seen as having only “mild to moderate” activity as asthma therapeutics (see Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2, April 1997 NHLBI, NIH, Publication No. 97-4051, p. 32).
Among the quinoline antimalarials (e.g., quinine, chloroquine, amodiaquine, primaquine and mefloquine) there are certain compounds which are used as anti-inflammatory therapeutics (Antimalarial pharmacokinetics and treatment regimens, N J White (1992) Br. J. Clin. Pharmac., 34, 1–10). The 4-aminoquinoline class of anti-malarial compounds, in particular chloroquine and hydroxychloroquine have been used as anti-inflammatory and immunomodulatory agents in the treatment of rheumatoid arthritis and systemic lupus erthematosus for the past 20 years. These compounds increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases, lipid mobilization and antigenic processing (Mechanism of Action of Hydroxychloroquine as an Antirheumatic Drug, R I Fox (1993) Seminars in Arthritis and Rheumatism, 23, Suppl. 1, 82–91). Although these drugs have been known for several years, they have been administered heretofore orally for specifically treating anti-inflammatory conditions.
Recently, U.S. Pat. No. 4,181,725 to , Voorhees, et al. discloses the use of various drugs, such as chloroquine and hydroxychloroquine, for the treatment of skin proliferative diseases, such as psoriasis.
However, until now, no one has suggested administering these drugs locally for treating anti-inflammatory conditions which are not on the surface of the skin.
For example, as a systemically delivered immunomodulatory agent, hydroxychloroouine (HCQ) in particular has been demonstrated to have multiple anti-inflammatory effects and has been shown to have significant advantages in safety over the other available systemic anti-inflammatory agents mentioned above. For this reason, HCQ is the only systemic anti-inflammatory that has been approved, by both the FDA's Pulmonary Branch and an independent Investigational Review Board, for use in a double-blind trial in non-oral glucocorticosteroid-dependent asthmatic subjects (Hydroxychloroquine improves airflow and lowers circulating IgE levels in subjects with moderate symptomatic asthma, B. L. Charous, E. F. Halpern, G. C. Steven (1998), J. Allergy Clin. Immunol., 102, 198–203).
The current delivery methods for HCQ, such as oral administration, have several drawbacks, however. When delivered orally, the rate of onset is slow, and the agent actively concentrates in organs other than the target organ. As a consequence, a relatively high dosage and long term treatment are required. In addition to added cost and low efficiency, such a high-dosage, long-term treatment carries a risk, however slight, of ocular toxicity. (Antimalarial ocular toxicity, a critical appraisal, D. A. Albert, L. K. L. Debois, K. F. Lu (1998) J. of Clin. Rheumatol. (US) 4, 57–62.)
Despite the drawbacks, the anti-malarials, such as HCQ, have only been administered systemically, e.g., orally for treating anti-inflammatory conditions, such as asthma, and topically on the surface of the skin for treating dermatological diseases, such as proliferative skin diseases. No one heretofore even suggested that they be administered by other means for treating anti-inflammatory conditions, especially since a change in the mode of administration may substantially alter drug action.
The choice of drug delivery methods requires full appreciation of the pharmacologic activities of the agent including tissue distribution, metabolism and cellular effects as well as an understanding of the interaction of the drug with the specific underlying pathological processes of the disease under treatment. Proof of efficacy by one route of administration does not imply the presence of a desired drug effect when administered via an alternate route of administration. For example, see, Fahy, et al. in Am. J. Respir. Crit. Care Med., 1999, 160:1023–1027 which showed that intravenous administration of Anti IgE(E25) was effective for treating allergic asthma, but that a different route of administration, viz., inhalation, was virtually ineffective in treating allergic asthma. Moreover, a change in drug administration from systemic to methods designed to target drug delivery to affected tissues may substantially increase drug effects in selective tissue, but carries the risk of increased local toxicity. It may promote salutary effects such as decreasing the time to onset of action, but may result in loss of overall efficacy due to the restricted nature of tissue distribution.
Because the route of drug administration determines bioavailability and tissue levels and distribution, change in delivery may modify fundamentally the location, nature, extent and duration of anti-inflammatory actions, as well as alter dosing requirements and toxicities. As the skilled artisan is well aware, there can be no assumption that if a drug works when administered one way, it will work when administered another way, particularly when drugs are delivered to mucosal and serosal tissues. In effect, any change in administration method may cause undesired effects.
However, the present inventor has shown that when anti-malarials exhibiting anti-inflammatory activity are administered locally to a patient in need of treatment, the anti-malarials agents were unexpectedly more efficacious in treating inflammatory conditions than when administered systemically.